The RBL-5 lymphoma has previously been shown to be highly sensitive to natural hybrid resistance, under the control of H-2 genes at the host level. The present study of the RBL-5 tumour was focused on progression towards disseminated growth after intravenous (i.v.) inoculation in the syngeneic host and the possible influence of the MHC genes at the tumour cell level. Data are presented to illustrate that there is no obligatory association between reduced H-2 expression and increased malignancy, and that the opposite may be observed. The wild type RBL-5 line expressed readily detectable H-2K and H-2D products, and a highly malignant subline selected for lung colonization in vivo did not show any reduction but rather enhanced expression of these antigens. Depending on the inoculum size, this selected subline caused disseminated lymphoma (in the liver, spleen and lungs) at a faster rate or higher frequency of animals than the wild type line. Conversely, a subline selected for reduced H-2 expression in vitro, by repeated treatments with antibody and complement, failed to form colonies in any organ after i.v. inoculation, even if the cell dose was increased by more than 100-fold in comparison with the threshold dose for the wild type line. This H-2-deficient subline was completely resistant to syngeneic RBL-5 immune cytotoxic T lymphocytes (CTL). Clones isolated during selection of the subline showed different degrees of reduction in sensitivity to H-2 specific CTL, but an inverse pattern of sensitivity to poly I:C induced natural killer (NK) cells. Selection pressure imposed by NK-mediated elimination directed preferentially against cells with reduced H-2 expression may be one explanation of why the gain of histocompatibility antigens is associated with tumour progression in some systems. Another important implication taken up for discussion is that tests for the effect of MHC modulation on tumour growth or immunotherapy require careful experimental design, to cover the action of different effector mechanisms in vivo.